Process for the preparation of fluorobenzyl derivatives

Abstract

A fluorine-containing benzonitrile derivative (formula 1) is subjected to a reduction reaction to obtain a fluorine-containing benzylamine derivative (formula 2), and the amino group in said fluorine-containing benzylamine derivative is replaced with a hydroxyl group to obtain a fluorine-containing benzyl alcohol derivative (formula 3):wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, and m is an integer of from 0 to 4.

What is claimed is:  
     
       1. A process for producing a fluorine-containing benzyl alcohol derivative represented by the following general formula (3), which comprises subjecting a fluorine-containing benzonitrile derivative represented by the following general formula (1) to a reduction reaction with a reducing agent consisting essentially of hydrogen in the presence of a Raney nickel catalyst or a Raney cobalt catalyst in a non-polar solvent to obtain a fluorine-containing benzylamine derivative represented by the following general formula (2), and replacing the amino group in said fluorine-containing benzylamine derivative with a hydroxyl group by one of the following processes: 
       Process 1: a process wherein the compound (2) is converted to a tertiary amine compound, ethyl bromide is reacted therewith, and sodium acetate is reacted therewith under an alkali condition in a methanol solvent,  
       Process 2: a process wherein the compound (2) is reacted with 2,4,5-triphenylpyrylium tetrafluoroborate salt and sodium (2-hydroxymethyl)benzoate in the presence of a phase transfer catalyst,  
       Process 3: a process wherein the compound (2) is reacted with an acid and an alkali nitrite,  
       Process 4: a process wherein a reaction is carried out in the same manner as in Process 3, employing a carboxylic acid compound as the acid, and the obtained reaction product is hydrolyzed,                    
       wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, and m is an integer of from 0 to 4. 
     
     
       2. The process for producing a fluorine-containing benzyl alcohol derivative according to  claim 1 , which comprises reacting the fluorine-containing benzylamine derivative represented by the general formula (2) with an acid and an alkali nitrite, followed by a hydrolysis as the case requires, to replace the amino group with a hydroxyl group. 
     
     
       3. A process for producing a fluorine-containing benzylamine derivative represented by the following general formula (2), which comprises reacting a fluorine-containing benzonitrile derivative represented by the following general formula (1) with a reducing agent consisting essentially of hydrogen in the presence of a Raney nickel catalyst or a Raney cobalt catalyst in a non-polar solvent:                    
       wherein X is halogen atom, when m is an integer of  2  or more, each X may be the same or different, and m is an integer of from 0 to 4. 
     
     
       4. A process for producing a fluorine-containing benzyl alcohol derivative represented by the following general formula (3), which comprises reacting a fluorine-containing benzylamine derivative represented by the following general formula (2) with an acid and an alkali nitrite, followed by hydrolysis as the case requires:                    
       wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, and m is an integer of from 0 to 4. 
     
     
       5. A process for producing a fluorine-containing benzyl alcohol represented by the following general formula (3) and a fluorine-containing benzyl ester derivative represented by the following general formula (5), which comprises subjecting a fluorine-containing benzonitrile derivative represented by the following general formula (1) to a reduction reaction with a reducing agent consisting essentially of hydrogen in the presence of a Raney nickel catalyst or a Raney cobalt catalyst in a non-polar solvent to obtain a fluorine-containing benzylamine derivative represented by the following general formula (2), and reacting said fluorine-containing benzylamine derivative with a carboxylic acid compound represented by the following general formula (4) and an alkali nitrite:                    
       wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, m is an integer of from 0 to 4, and R is a linear alkyl group which may have a substituent, or a branched alkyl group which may have a substituent. 
     
     
       6. A process for producing a fluorine-containing benzyl alcohol derivative represented by the following general formula (3) and a fluorine-containing benzyl ester derivative represented by the following general formula (5), which comprises reacting a fluorine-containing benzylamine derivative represented by the following general formula (2) with a carboxylic acid compound represented by the following general formula (4) and an alkali nitrite:                    
       wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, m is an integer of from 0 to 4, and R is a linear alkyl group which may have a substituent, or a branched alkyl group which may have a substituent. 
     
     
       7. A process for producing a fluorine-containing benzyl alcohol derivative represented by the following general formula (3), which comprises reacting a fluorine-containing benzylamine derivative represented by the following general formula (2) with a carboxylic acid compound represented by the following general formula (4) and an alkali nitrite, to obtain a reaction product containing the fluorine-containing benzyl alcohol derivative represented by the following general formula (3) and a fluorine-containing benzyl ester derivative represented by the following general formula (5), followed by hydrolysis of said reaction product comprising a benzyl ester derivative represented by the general formula (5):                    
       wherein X is a halogen atom, when m is an integer of 2 or more, each X may be the same or different, m is an integer of from 0 to 4, and R is a linear alkyl group which may have a substituent, or a branched alkyl group which may have a substituent. 
     
     
       8. A 2,6-difluorobenzyl ester derivative represented by the following general formula (5A):                    
       wherein R is a linear C 2-6 -alkyl group which may have a substituent, or a branched C 2-6 -alkyl group which may have a substituent.